Between-centre differences and treatment effects in randomized controlled trials: A case study in traumatic brain injury

BACKGROUND: In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI. METHODS: We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs. RESULTS: In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26). CONCLUSION: Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI

Using Abbreviated Injury Scale (AIS) codes to classify Computed Tomography (CT) features in the Marshall System

<p>Abstract</p> <p>Background</p> <p>The purpose of Abbreviated Injury Scale (AIS) is to code various types of Traumatic Brain Injuries (TBI) based on their anatomical location and severity. The Marshall CT Classification is used to identify those subgroups of brain injured patients at higher risk of deterioration or mortality. The purpose of this study is to determine whether and how AIS coding can be translated to the Marshall Classification</p> <p>Methods</p> <p>Initially, a Marshall Class was allocated to each AIS code through cross-tabulation. This was agreed upon through several discussion meetings with experts from both fields (clinicians and AIS coders). Furthermore, in order to make this translation possible, some necessary assumptions with regards to coding and classification of mass lesions and brain swelling were essential which were all approved and made explicit.</p> <p>Results</p> <p>The proposed method involves two stages: firstly to determine all possible Marshall Classes which a given patient can attract based on allocated AIS codes; via cross-tabulation and secondly to assign one Marshall Class to each patient through an algorithm.</p> <p>Conclusion</p> <p>This method can be easily programmed in computer softwares and it would enable future important TBI research programs using trauma registry data.</p

Intracranial bleeding in patients with traumatic brain injury: A prognostic study

BACKGROUND: Intracranial bleeding (IB) is a common and serious consequence of traumatic brain injury (TBI). IB can be classified according to the location into: epidural haemorrhage (EDH) subdural haemorrhage (SDH) intraparenchymal haemorrhage (IPH) and subarachnoid haemorrhage (SAH). Studies involving repeated CT scanning of TBI patients have found that IB can develop or expand in the 48 hours after injury. If IB enlarges after hospital admission and larger bleeds have a worse prognosis, this would provide a therapeutic rationale for treatments to prevent increase in the extent of bleeding. We analysed data from the Trauma Audit & Research Network (TARN), a large European trauma registry, to evaluate the association between the size of IB and mortality in patients with TBI. METHODS: We analysed 13,962 patients presenting to TARN participating hospitals between 2001 and 2008 with a Glasgow Coma Score (GCS) less than 15 at presentation or any head injury with Abbreviated Injury Scale (AIS) severity code 3 and above. The extent of intracranial bleeding was determined by the AIS code. Potential confounders were age, presenting Glasgow Coma Score, mechanism of injury, presence and nature of other brain injuries, and presence of extra-cranial injuries. The outcomes were in-hospital mortality and haematoma evacuation. We conducted a multivariable logistic regression analysis to evaluate the independent effect of large and small size of IB, in comparison with no bleeding, on patient outcomes. We also conducted a multivariable logistic regression analysis to assess the independent effect on mortality of large IB in comparison with small IB. RESULTS: Almost 46% of patients had at some type of IB. Subdural haemorrhages were present in 30% of the patients, with epidural and intraparenchymal present in approximately 22% each. After adjusting for potential confounders, we found that large IB, wherever located, was associated with increased mortality in comparison with no bleeding. We also found that large IB was associated with an increased risk of mortality in comparison with small IB. The odds ratio for mortality for large SDH, IPH and EDH, in comparison with small bleeds, were: 3.41 (95% CI: 2.684.33), 3.47 (95% CI: 2.265.33) and 2.86 (95% CI: 1.864.38) respectively. CONCLUSION: Large EDH, SDH and IPH are associated with a substantially higher probability of hospital mortality in comparison with small IB. However, the limitations of our data, such as the large proportion of missing data and lack of data on other confounding factors, such as localization of the bleeding, make the results of this report only explanatory. Future studies should also evaluate the effect of IB size on functional outcomes

Use of the Oxford Handicap Scale at hospital discharge to predict Glasgow Outcome Scale at 6 months in patients with traumatic brain injury

BACKGROUND: Traumatic brain injury (TBI) is an important cause of acquired disability. In evaluating the effectiveness of clinical interventions for TBI it is important to measure disability accurately. The Glasgow Outcome Scale (GOS) is the most widely used outcome measure in randomised controlled trials (RCTs) in TBI patients. However GOS measurement is generally collected at 6 months after discharge when loss to follow up could have occurred. The objectives of this study were to evaluate the association and predictive validity between a simple disability scale at hospital discharge, the Oxford Handicap Scale (OHS), and the GOS at 6 months among TBI patients. METHODS: The study was a secondary analysis of a randomised clinical trial among TBI patients (MRC CRASH Trial). A Spearman correlation was estimated to evaluate the association between the OHS and GOS. The validity of different dichotomies of the OHS for predicting GOS at 6 months was assessed by calculating sensitivity, specificity and the C statistic. Uni and multivariate logistic regression models were fitted including OHS as explanatory variable. For each model we analysed its discrimination and calibration. RESULTS: We found that the OHS is highly correlated with GOS at 6 months (spearman correlation 0.75) with evidence of a linear relationship between the two scales. The OHS dichotomy that separates patients with severe dependency or death showed the greatest discrimination (C statistic: 84.3). Among survivors at hospital discharge the OHS showed a very good discrimination (C statistic 0.78) and excellent calibration when used to predict GOS outcome at 6 months. CONCLUSION: We have shown that the OHS, a simple disability scale available at hospital discharge can predict disability accurately, according to the GOS, at 6 months. OHS could be used to improve the design and analysis of clinical trials in TBI patients and may also provide a valuable clinical tool for physicians to improve communication with patients and relatives when assessing a patient's prognosis at hospital discharge

Focal brain trauma in the cryogenic lesion model in mice

The method to induce unilateral cryogenic lesions was first described in 1958 by Klatzo. We describe here an adaptation of this model that allows reliable measurement of lesion volume and vasogenic edema by 2, 3, 5-triphenyltetrazolium chloride-staining and Evans blue extravasation in mice. A copper or aluminium cylinder with a tip diameter of 2.5 mm is cooled with liquid nitrogen and placed on the exposed skull bone over the parietal cortex (coordinates from bregma: 1.5 mm posterior, 1.5 mm lateral). The tip diameter and the contact time between the tip and the parietal skull determine the extent of cryolesion. Due to an early damage of the blood brain barrier, the cryogenic cortical injury is characterized by vasogenic edema, marked brain swelling, and inflammation. The lesion grows during the first 24 hours, a process involving complex interactions between endothelial cells, immune cells, cerebral blood flow, and the intracranial pressure. These contribute substantially to the damage from the initial injury. The major advantage of the cryogenic lesion model is the circumscribed and highly reproducible lesion size and location

An improved parameter estimation and comparison for soft tissue constitutive models containing an exponential function

Motivated by the well-known result that stiffness of soft tissue is proportional to the stress, many of the constitutive laws for soft tissues contain an exponential function. In this work, we analyze properties of the exponential function and how it affects the estimation and comparison of elastic parameters for soft tissues. In particular, we find that as a consequence of the exponential function there are lines of high covariance in the elastic parameter space. As a result, one can have widely varying mechanical parameters defining the tissue stiffness but similar effective stress–strain responses. Drawing from elementary algebra, we propose simple changes in the norm and the parameter space, which significantly improve the convergence of parameter estimation and robustness in the presence of noise. More importantly, we demonstrate that these changes improve the conditioning of the problem and provide a more robust solution in the case of heterogeneous material by reducing the chances of getting trapped in a local minima. Based upon the new insight, we also propose a transformed parameter space which will allow for rational parameter comparison and avoid misleading conclusions regarding soft tissue mechanics

External validation of the Scandinavian guidelines for management of minimal, mild and moderate head injuries in children

© 2018 The Author(s). Background: Clinical decision rules (CDRs) aid in the management of children with traumatic brain injury (TBI). Recently, the Scandinavian Neurotrauma Committee (SNC) has published practical, evidence-based guidelines for children with Glasgow Coma Scale (GCS) scores of 9-15. This study aims to validate these guidelines and to compare them with other CDRs. Methods: A large prospective cohort of children (< 18 years) with TBI of all severities, from ten Australian and New Zealand hospitals, was used to assess the SNC guidelines. Firstly, a validation study was performed according to the inclusion and exclusion criteria of the SNC guideline. Secondly, we compared the accuracy of SNC, CATCH, CHALICE and PECARN CDRs in patients with GCS 13-15 only. Diagnostic accuracy was calculated for outcome measures of need for neurosurgery, clinically important TBI (ciTBI) and brain injury on CT. Results: The SNC guideline could be applied to 19,007/20,137 of patients (94.4%) in the validation process. The frequency of ciTBI decreased significantly with stratification by decreasing risk according to the SNC guideline. Sensitivities for the detection of neurosurgery, ciTBI and brain injury on CT were 100.0% (95% CI 89.1-100.0; 32/32), 97.8% (94.5-99.4; 179/183) and 95% (95% CI 91.6-97.2; 262/276), respectively, with a CT/admission rate of 42% (mandatory CT rate of 5%, 18% CT or admission and 19% only admission). Four patients with ciTBI were missed; none needed specific intervention. In the homogenous comparison cohort of 18,913 children, the SNC guideline performed similar to the PECARN CDR, when compared with the other CDRs. Conclusion: The SNC guideline showed a high accuracy in a large external validation cohort and compares well with published CDRs for the management of paediatric TBI

The Glasgow Outcome Scale -- 40 years of application and refinement

The Glasgow Outcome Scale (GOS) was first published in 1975 by Bryan Jennett and Michael Bond. With over 4,000 citations to the original paper, it is the most highly cited outcome measure in studies of brain injury and the second most-cited paper in clinical neurosurgery. The original GOS and the subsequently developed extended GOS (GOSE) are recommended by several national bodies as the outcome measure for major trauma and for head injury. The enduring appeal of the GOS is linked to its simplicity, short administration time, reliability and validity, stability, flexibility of administration (face-to-face, over the telephone and by post), cost-free availability and ease of access. These benefits apply to other derivatives of the scale, including the Glasgow Outcome at Discharge Scale (GODS) and the GOS paediatric revision. The GOS was devised to provide an overview of outcome and to focus on social recovery. Since the initial development of the GOS, there has been an increasing focus on the multidimensional nature of outcome after head injury. This Review charts the development of the GOS, its refinement and usage over the past 40 years, and considers its current and future roles in developing an understanding of brain injury